Advanced

Immune Responses Aginst Aldehyde Modified Extracellular Matrix in Atherosclerosis

Dunér, Pontus LU (2009) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2009:86.
Abstract
Atherosclerosis is a chronic inflammatory disease and the leading cause of myocardial infarction and stroke. Accumulation, aggregation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. The oxidation of LDL generates reactive aldehydes, including malondialdehyde (MDA) that modifies ApoB in LDL. Immune responses against MDA-modified epitopes on ApoB have been shown to be linked to atherosclerotic disease. This thesis is focused on the possibility that LDL oxidation result in the release of MDA that modified surrounding extracellular matrix (ECM) proteins. These modifications may subsequently target immune responses against the plaque ECM and influence the atherosclerotic... (More)
Atherosclerosis is a chronic inflammatory disease and the leading cause of myocardial infarction and stroke. Accumulation, aggregation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. The oxidation of LDL generates reactive aldehydes, including malondialdehyde (MDA) that modifies ApoB in LDL. Immune responses against MDA-modified epitopes on ApoB have been shown to be linked to atherosclerotic disease. This thesis is focused on the possibility that LDL oxidation result in the release of MDA that modified surrounding extracellular matrix (ECM) proteins. These modifications may subsequently target immune responses against the plaque ECM and influence the atherosclerotic process. Our studies provide evidence for the presence of MDA-modifications on ECM proteins during atherosclerosis. We also show that antibodies against several MDA-modified ECM proteins are present in human plasma. A prospective clinical study showed that subjects that later suffered from acute cardiovascular events had significantly lower IgG and IgM antibody levels against MDA-modified fibronectin. These epidemiological results indicate that immune responses against MDA-modified fibronectin may have protective effects in atherosclerotic disease. To investigate the functional role of immune responses against modified matrix proteins in atherosclerosis, we immunized Apoe-/- mice with two different MDA-modified matrix proteins to which we had found antibodies in human plasma. MDA-modified fibronectin immunization significantly decreased the atherosclerotic plaque development in both aorta and in subvalvular lesions, while MDA-modified laminin resulted in increased plaque development. Finally we show that injection of Alum, an adjuvant commonly used in vaccines, results in LDL oxidation and aldehyde generation at the injection site. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Newby, Andrew C, Bristol Heart Institute, Bristol Rayal Infirary, Bristol, UK
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Plaque Malondialdehyde Atherosclerosis Autoantibodies Extracellular Matrix Fibronectin Laminin oxidized LDL T regulatory cells Alum
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2009:86
pages
113 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Midicinska Klinikens aula, ingång 35, Universitetssjukhuset MAS, Malmö
defense date
2009-10-09 13:00
ISSN
1652-8220
ISBN
978-91-86253-74-5
language
English
LU publication?
yes
id
021edcc6-24a1-4cc2-9fba-547d3e7d0081 (old id 1478513)
date added to LUP
2009-09-21 10:35:57
date last changed
2016-09-19 08:44:50
@phdthesis{021edcc6-24a1-4cc2-9fba-547d3e7d0081,
  abstract     = {Atherosclerosis is a chronic inflammatory disease and the leading cause of myocardial infarction and stroke. Accumulation, aggregation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. The oxidation of LDL generates reactive aldehydes, including malondialdehyde (MDA) that modifies ApoB in LDL. Immune responses against MDA-modified epitopes on ApoB have been shown to be linked to atherosclerotic disease. This thesis is focused on the possibility that LDL oxidation result in the release of MDA that modified surrounding extracellular matrix (ECM) proteins. These modifications may subsequently target immune responses against the plaque ECM and influence the atherosclerotic process. Our studies provide evidence for the presence of MDA-modifications on ECM proteins during atherosclerosis. We also show that antibodies against several MDA-modified ECM proteins are present in human plasma. A prospective clinical study showed that subjects that later suffered from acute cardiovascular events had significantly lower IgG and IgM antibody levels against MDA-modified fibronectin. These epidemiological results indicate that immune responses against MDA-modified fibronectin may have protective effects in atherosclerotic disease. To investigate the functional role of immune responses against modified matrix proteins in atherosclerosis, we immunized Apoe-/- mice with two different MDA-modified matrix proteins to which we had found antibodies in human plasma. MDA-modified fibronectin immunization significantly decreased the atherosclerotic plaque development in both aorta and in subvalvular lesions, while MDA-modified laminin resulted in increased plaque development. Finally we show that injection of Alum, an adjuvant commonly used in vaccines, results in LDL oxidation and aldehyde generation at the injection site.},
  author       = {Dunér, Pontus},
  isbn         = {978-91-86253-74-5},
  issn         = {1652-8220},
  keyword      = {Plaque
Malondialdehyde
Atherosclerosis
Autoantibodies
Extracellular Matrix
Fibronectin
Laminin
oxidized LDL
T regulatory cells
Alum},
  language     = {eng},
  pages        = {113},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Immune Responses Aginst Aldehyde Modified Extracellular Matrix in Atherosclerosis},
  volume       = {2009:86},
  year         = {2009},
}